Concerted action of coagulation factors on cell survival

Versteeg, Henri H.; Richel, Dick J.; Peppelenbosch, Maikel P.; Spek, C. Arnold

doi:10.1111/j.1538-7836.2004.00691.x

Cited by 5 publications

(4 citation statements)

References 7 publications

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“…This association has proved to be functionally relevant both for primary tumor growth and late stages of metastasis as cells overexpressing TF become more angiogenic and metastatic through TF-mediated thrombin generation, fibrin deposition, and platelet activation. Additionally, TF can induce signaling events mediated by protease-activated receptor-2 and, thus, may contribute to cancer progression independently of coagulation (34,42,43). Tumor growth appears to be facilitated by TF expression (34) via mechanisms that may involve PAR-mediated signaling events (42).…”

Section: Discussionmentioning

confidence: 99%

Cell Surface Proteomics Identifies Molecules Functionally Linked to Tumor Cell Intravasation

Conn

Madsen

Cravatt

et al. 2008

Journal of Biological Chemistry

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In order to better understand the molecular and cellular determinants of tumor cell intravasation, our laboratory has generated a pair of congenic human HT-1080 fibrosarcoma variants (i.e. HT-hi/diss and HT-lo/diss) differing 50 -100-fold in their ability to intravasate and disseminate. To investigate the molecular differences underlying the distinct dissemination capacities of these HT-1080 variants, we performed a comparative analysis of the cell surface proteomes of HT-hi/diss and HT-lo/diss. Cell membrane proteins were enriched by biotinylation and avidin precipitation and analyzed by tandem mass spectrometry employing multidimensional protein identification technology. By this approach, 47 cell surface-associated molecules were identified as differentially expressed between the HT-1080 intravasation variants. From these candidates, four targets (i.e. TIMP-2, NCAM-1, JAM-C, and tissue factor (TF)) were selected for further biochemical validation and in vivo functional verification. Western blot analysis of the cell surface enriched fractions confirmed the proteomic array data, demonstrating that, in vitro, TIMP-2 protein was increased in the HT-lo/diss variant, whereas NCAM-1, JAM-C, and TF levels were increased in the HT-hi/diss variant. Corresponding in vivo differences in levels of TIMP-2, JAM-C, and TF were demonstrated in primary tumors grown in the chick embryo. Finally, functional inhibition of one selected protein (i.e. TF) by small interfering RNA silencing or ligation with a function-blocking antibody significantly reduced HT-hi/diss intravasation, thus clearly implicating TF in the early steps of tumor cell dissemination. Overall, our cell surface proteomic analysis provides a powerful tool for identification of specific cell membrane molecules that contribute functionally to intravasation and metastasis in vivo.One of the early and possibly rate-limiting steps in cancer progression from a localized tumor to systemic metastatic disease is intravasation (i.e. the entry of metastatic cells into the vasculature) (1-5). Molecules involved in intravasation represent attractive therapeutic targets, since preventing or inhibiting this process would confine tumor cells to their primary site and provide a more focused target for clinical intervention (6). To identify cellular attributes that functionally contribute to tumor cell intravasation and metastasis, including escape from the primary site, invasion of local stoma, and entry into the vasculature, we have employed a pair of congenic human fibrosarcoma HT-1080 cell variants, differing 50 -100-fold in their ability to intravasate and disseminate (HT-hi/diss and HT-lo/diss) while having similar capacities to form primary tumors (7). These cell variants display a distinct differential during spontaneous metastasis but behave comparably in experimental metastasis models where cells are inoculated intravenously and only the later steps of the metastatic cascade are recapitulated. Therefore, comparative analysis of the HT-hi/diss and HT-lo/diss variants can...

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Section: Discussionmentioning

confidence: 99%

Cell Surface Proteomics Identifies Molecules Functionally Linked to Tumor Cell Intravasation

Conn

Madsen

Cravatt

et al. 2008

Journal of Biological Chemistry

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“…6A). Furthermore, whereas FXa induces cell survival in BHK TF cells [24], it did not significantly change cell survival in HaCaT cells. Thrombin, which also induces cell survival in BHK TF , led to cell survival in HaCaT cells as well (Fig.…”

Section: Resultsmentioning

confidence: 99%

TF:FVIIa‐specific activation of CREB upregulates proapoptotic proteins via protease‐activated receptor‐2

Versteeg

Borensztajn

Kerver

et al. 2008

Journal of Thrombosis and Haemostasis

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To cite this article: Versteeg HH, Borensztajn KS, Kerver ME, Ruf W, Reitsma PH, Spek CA, Peppelenbosch MP. TF:FVIIa-specific activation of CREB upregulates proapoptotic proteins via protease activated receptor-2. J Thromb Haemost 2008; 6: 1550-7.Summary. Background: Tissue factor (TF) and factor (F) VIIa are the primary initiators of the coagulation cascade, but also promote non-hemostatic events, such as angiogenesis and tumor growth, via activation of protease activated receptor-2 (PAR2). Our previous findings indicated that the TF:FVIIa complex activates signal transducer and activator of transcription (STAT) signaling, leading to cell survival in TF-transfected baby hamster kidney (BHK) cells. Methods: Using BHK TF , keratinocytes (HaCaT) and human umbilical vein endothelial cells (HUVEC), FVIIa-induced phosphorylation and activation of the transcription factor cyclic AMP-responsive binding protein (CREB) were tested and compared to that elicited by thrombin and FXa. In addition, the effect of these factors on cell survival and expression of apoptosis-associated proteins was monitored. Results: Factor VIIa led to a TF-dependent, but TF cytoplasmic domain-independent phosphorylation and activation of CREB in BHK TF , HaCaT and HUVEC. CREB activation was sensitive to blockade of the extracellular-signal regulated kinase 1/2 pathway and PAR2. Surprisingly, FVIIa decreased cell survival in HaCaT cells but not other cell types and upregulated the pro-apoptotic proteins Bak and Puma in a CREB-dependent manner. Factor Xa, but not FIIa, induced phosphorylation of CREB, but did not have an effect on apoptosis. Conclusion: TF:FVIIa induces CREB phosphorylation and activation in several cell types, but TF:FVIIa induces pro-apoptotic proteins and apoptosis only in selected cell types.

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“…lack-of-anchorage-induced cell death, can be inhibited by FVIIa-induced activation of these pathways (41). Although FVIIa by itself may induce cell survival, inclusion of FXa in the ternary complex, or additional activation of thrombin may lead to an even more pronounced inhibition of apoptosis (42). As discussed above, FVIIa enhanced survival of BHK-TF have also been shown to proceed via a heterotrimeric G-protein-dependent Jak/STAT5 pathway leading to upregulation of the anti-apoptotic protein Bcl XL (38), suggesting that TF activates a variety of signaling events to induce an anti-apoptotic effect.…”

Section: Apoptosis Inhibitionmentioning

confidence: 99%

Tissue Factor signaling: a multi-faceted function in biological processes

Hengel

Versteeg²

2011

Front Biosci

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Tissue factor (TF), originally discovered to initiate coagulation, is more recently recognized to be involved in other biological processes, such as migration and anti-apoptosis. TF-mediated signaling regulates gene expression and protein synthesis, leading to alterations in cellular behavior. The proteolytic activity of factor VIIa (FVIIa), beta-1 integrin interaction and protease-activated receptor (PAR) activation are some of the key events involved in TF signaling. Post-translational modifications of TF may regulate signaling but this remains elusive. In vivo studies have established that TF signaling severely contributes to processes like angiogenesis, cancer growth and inflammation. This review focuses on the mechanism underlying TF-mediated intracellular signaling with its related physiological and mainly pathological consequences.

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Concerted action of coagulation factors on cell survival

Cited by 5 publications

References 7 publications

Cell Surface Proteomics Identifies Molecules Functionally Linked to Tumor Cell Intravasation

Cell Surface Proteomics Identifies Molecules Functionally Linked to Tumor Cell Intravasation

TF:FVIIa‐specific activation of CREB upregulates proapoptotic proteins via protease‐activated receptor‐2

Tissue Factor signaling: a multi-faceted function in biological processes

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